Voluntary sleep restriction is common; 30% of the US adult population reports <6 h of sleep per night, and those who do are 24% more likely to have cardiovascular disease and have twice the risk of hypertension. Sleep deprivation may be one of the commonest preventable cardiovascular risk factors. Prehypertension is also highly prevalent, affecting >25% of adults, and this population is at particularly high risk of developing frank hypertension and cardiovascular disease. The comorbidity of inadequate sleep and prehypertension is likely to be very common, with implications for frank hypertension and cardiovascular complications. No definitive experimental studies in humans show whether partial sleep deprivation indeed results in impaired cardiovascular function, nor are there conclusive experiments addressing the underlying physiologic and molecular mechanisms that may be involved, especially with regard to any changes in blood pressure. We propose to conduct a randomized, cross-over study in individuals with prehypertension, incorporating a 3-day acclimation period with 9 nights of sleep restricted to 4 hours per night. These data will be compared to a control/normal sleep sequence. Subjects will complete both sleep restriction and control sequences, separated by a 3-month washout period. Thus, each subject will serve as his or her own control in an experiment that closely matches real-world sleep restriction. We will combine this robust model with a state-of-the-art sleep monitoring system that provides continuous and accurate sleep/wake data in an unobtrusive way. We are currently using this model of sleep restriction in successful ongoing studies and have several decades of experience in conducting human studies of cardiovascular physiology. Comprehensive serial physiologic data will be complemented by detailed translational molecular studies of microvessels and adipocytes obtained by tissue biopsy before and after sleep restriction. Upon completion of these studies we will be able to ascertain: 1. The effects of sleep restriction on blood pressure throughout the entire 24-hour period 2. The effects of sleep restriction on neural circulatory control 3. The effects of sleep restriction on vascular function 4. The effects of slep restriction on systemic and adipose tissue inflammation Important strengths of this application include our compelling preliminary data, the ability to accomplish the specific aims while minimizing potential confounders, our focus on a group at high risk of developing frank hypertension and cardiovascular disease, the integration of widely accepted surrogates of cardiovascular risk with mechanistic molecular studies at the level of the vascular endothelial cell and the adipocyte, and a statistical plan that will provide a rich summary of the effects of sleep restriction on the four specific aims. Our long-term goal is to identify the fundamental biologic mechanisms that link sleep restriction to cardiovascular disease so as to define targets for interventions directed at reducing cardiovascular risk. PUBLIC HEALTH RELEVANCE: We propose to examine whether 9 nights of modest sleep restriction results in activation of cardiovascular disease mechanisms in individuals with prehypertension, thus potentially increasing the risk of frank hypertension and cardiovascular disease. These findings will help explain whether the reduced sleep duration in the general population may be contributing to the current epidemic of cardiovascular disease, and suggest strategies to reduce this risk.